Acta Anaesthesiol Scand 2014; 58: 1093–1100 Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12386

Hypothermia after cardiac arrest does not affect serum levels of neuron-specific enolase and protein S-100b R. Pfeifer, M. Franz and H. R. Figulla Clinic of Internal Medicine I, Jena University Hospital, Jena, Germany

Background: We investigated the brain-derived proteins neuron-specific enolase (NSE) and protein S-100b (S-100b) in survivors of cardiac arrest who had either received therapeutic hypothermia (TH) or had not. Methods: In a retrospective cohort study, we analysed serum levels of these two proteins over 5 days in 201 adult cardiac arrest survivors admitted to our intensive care unit between 2003 and 2010. These were all survivors that remained comatose and survived at least 48 h. Of these, 140 received therapeutic hypothermia (hypothermia group). The remainder received only standard therapy without hypothermia (normothermia group). Results: There was no difference in survival between the hypothermia and normothermia groups. At 4 weeks after arrest, 61 (43.6%) patients of the hypothermia group and 26 (42.6%) patients of the normothermia group were still alive with favourable to moderate neurological outcome (Cerebral Performance Category Scale 1–3). We observed no change in the mean serum levels of either protein between the two groups. Within each group, we found significantly higher serum levels of NSE and

T

herapeutic hypothermia (TH) improves survival and neurological recovery in comatose survivors of out-of-hospital cardiac arrest after ventricular fibrillation (VF).1,2 TH is therefore recommended as a treatment option in this field.3,4 Usually, TH is applied for 24 h with a target body core temperature of 33°C, and the patients are mechanically ventilated and receive sedative drugs for several days. It is therefore difficult, during hypothermia, to make an early estimation of patient neurological outcome by daily clinical neurological examination. Thus, predictors of neurological outcome are needed that are independent of sedation under these conditions. Such predictors include the brain-derived proteins neuron-specific enolase (NSE) and protein S-100b (S-100b). Both of these are widely used prognostic markers for evaluating the severity of hypoxic brain injury in coma-

S-100b in patients with unfavourable neurological outcome (Cerebral Performance Category Scale 4 and 5) than in those with moderate to favourable outcome. Cut-off levels 3 days after cardiac arrest predicting an unfavourable outcome were > 40 ng/ml for NSE [specificity 95.2%, Sensitivity 74.1%, areas under the curve (AUC):0.889], false positive rate 4 [confidence interval (CI): 0.0131–0.1175] and > 1.03 μg/1 for S-100b (specificity 95.6%, Sensitivity 57.8%, AUC: 0.875) false positive rate 3 (CI: 0.0091–01218). Conclusions: Additional application of TH was not associated with significant changes in serum levels of NSE and S-100b in comatose survivors of cardiac arrest, compared to those treated without TH. Accepted for publication 7 July 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

tose survivors of cardiac arrest (CA).5–8 Before widespread use of TH, NSE serum levels ≥ 33 ng/ml measured within the first 72 h after restoration of spontaneous circulation (ROSC) were thought to be a reliable predictor of poor neurological outcome.6,7,9–11 This has become controversial however.7,8,12 Furthermore, NSE serum levels significantly decline in CA survivors receiving TH in some study.12–14 In others, neither protein appears sufficient to predict neurological outcome after CA under TH.15,16 A recent multicentre trial showed no improvement in survival and neurological outcome in CA survivors treated with a target body core temperature of 33°C, compared to 36°C.17 Against this background, we performed a retrospective analysis focusing on the question of whether the application of TH really affects NSE and S-100b serum concentrations in CA survivors.

1093 bs_bs_banner

R. Pfeifer et al.

Material and methods Our study included 201 comatose adult patients who had suffered an in- or out-of-hospital nontraumatic cardiac arrest. These were patients admitted to our intensive care unit (ICU) between January 2003 and June 2010. We excluded patients who reacted adequately during a 1 h observation phase without sedation and patients who died during the first 48 h after CA. TH was applied to 140 patients (30 female, 110 male, mean age: 63.2 ± 14.4 years), while 61 (24 female, 37 male, mean age: 67.8 ± 14.2 years) received comparable intensive care therapy without hypothermia. Retrospective data allocation and analysis was approved by the local ethics committee of the Jena University Hospital in 2005, Proc. Nr. 1558-06/05. The same ethics committee approved the retrospective data analysis of CA patients treated with hypothermia in 2005, Proc. Nr 1553-05/05. In 2007, the ethic committee approved our participation in a nationwide study about the use of therapeutic hypothermia after in-hospital CA. Proc. Nr. 2066-07/07. Moreover, written informed consent was given during ICU treatment by next of kin or by a legal advisor. We applied TH according to our 2011 published criteria.18 These criteria were continuously adapted over the entire course of the study to accord with the recommendations of the European Resuscitation Council (ERC).3,4 We thus did not initially (from 2003 to 2006) apply TH to CA survivors with unobserved VF, asystole and pulse-less electric activity, in-hospital CA and patients anoxic for an unknown period. Thereafter, TH was applied to patients with these conditions. The application or not of TH was decided by the duty doctor in accordance with the inclusion criteria then prevailing (Table 1). To assess NSE and S-100b serum concentrations, blood samples were taken, usually once daily, according to the routine of laboratory work. The first was taken immediately on ICU admission and then subsequently until 5 days after ROSC. Serum measurements were made with a commercial immunoluminometric assay with a LIAISON analyser (LIAISON Sangtec 100R, AB Sangtec Medical, POB 20045, 16102 Bromma, Sweden). NSE measurement is routinely available every day in our hospital. To reduce costs, S-100b serum concentration was not measured daily. After centrifugation, serum was frozen at −20°C, and up to 100 samples were accumulated before analysis. We accepted the manufacturer’s reference values for the serum concentrations

1094

Table 1 Exclusion criteria for TH after CA during the whole allocation time 2003–2010. Exclusion criteria

Number in %

Time delay between ROSC and possible start of hypothermia > 6 h Haemodynamically/respiratory instable patient Unknown time of hypoxia/duration of CPR/unobserved CA Recurring ventricular arrhythmia Patient under court-ordered guardianship In-hospital CA*

25% 17% 15% 8% 7% 28%

*Survivors with in-hospital CA excluded from the application of TH in the first years. Later, TH was applied after in-hospital CA, too, because our ICU took part in a nationwide German investigation on the use of hypothermia after in-hospital-CA. ROSC, restoration of spontaneous circulation; CPR, cardiopulmonary resuscitation; TH, therapeutic hypothermia; CA, cardiac arrest; ICU, intensive care unit.

in healthy people, the manufacturer terms 12.5 ng/ml for NSE and 0.15 μg/l for S-100b. These values fall within the 95% percentile of all serum concentrations from healthy people. To avoid using haemolytic serum samples, we routinely measured the serum level of free haemoglobin and of NSE simultaneously. The NSE and S-100b serum levels measured did not influence therapeutic decisions during the first 7 days after ROSC. Both groups received similar intensive care in accordance with generally accepted international standards and guidelines. TH was applied either by surface cooling or intravascular cooling. The aim was to maintain body core temperature within the narrow range 33 ± 0.5°C for 24 h. Body core temperature was measured with a bladder-temperature probe. All patients were deeply sedated during TH. Re-warming was achieved passively in surface-cooled patients and actively (0.3°C/h) in intravascularly cooled patients. Patients, who overheated, body temperature > 37.5°C, after hypothermia and in the normothermia group, were cooled externally with crushed ice or received antipyretics. Maintenance to the target of ≤ 37.5°C was continued until 72 h after ROSC in both groups. After 4 weeks, we classified the patients according to the Pittsburgh Cerebral Performance Category Scale (CPC).19 We divided the patients into two groups based on significant differences in long-term prognosis and from the ethical point of view. These were patients with poor outcome, i.e. those who died or remained comatose (CPC 4 and 5) and those who had good to moderate neurological recovery, i.e.

NSE and S-100b during hypothermia after CA Table 2 Baseline characteristics of the hypothermia group (HG) and the normothermia group (NG).

Mean age (years) Male n SAPS II Factors at resuscitation Ventricular fibrillation n Length of anoxia (min.) Duration of CPR (min.) OHCA n Cause of cardiac arrest Cardiovascular diseases n Length of unconsciousness (days) CPC after 4 weeks n CPC 1 CPC 2 CPC 3 CPC 4 CPC 5

NG

HG

(n = 61)

(n = 140)

P-value

67.8 ± 14.4 36 (59%) 62.3 ± 14.9

63.2 ± 14.2 110 (78.6%) 58 ± 17.0

0.012* 0.006 0.121

26 (42.6%) 5.2 ± 4.4 21.0 ± 18.9 26 (42.6%)

72 (51.1%) 6.2 ± 4.7 22.8 ± 14.3 95 (67.9%)

0.248 0.268 0.072 0.001*

38 (61.3%) 10.1 ± 10.9

102 (72.9%) 8.0 ± 7.2

0.133 0.160

5 (8.2%) 13 (21.3%) 8 (13.1%) 9 (14.8%) 26 (42.6%)

23 (16.4%) 27 (19.3%) 11 (7.9%) 13 (9.3%) 66 (47.1%)

1.00 – –

*Significant differences between the two therapeutic groups. SAPS, simplified acute physiology score; CPR, cardiopulmonary resuscitation; OHCA, out-of-hospital cardiac arrest; CPC, Cerebral Performance Category Scale; n, number of participants.

recovery of at least cognitive brain function and survival with neurological disabilities of variable severity or without any neurological impairment (CPC 3–1).

Statistical analysis We analysed the data using SPSS version 20 (SPSS Inc., Chicago, IL, USA). Data were expressed as mean ± standard deviation. Categorical data were represented as counts or percentages. We tested normality of distributions by Kolmogorov–Smirnov test. Where the distributions were normal, we applied two-tailed t-tests for testing differences between groups. If they were not, we used the Mann–Whitney U-test. Categorical variables were tested using the chi squared test. The sensitivity and specificity of NSE and S-100b threshold values for predicting unfavourable neurological outcome were calculated using receiver operating characteristic curves (ROC). Sensitivity, specificity, false positive rate (1-specificity) and predictive values were estimated for this defined cut-offs along with exact 95% confidence intervals (CI) assuming a binominal distribution. NSE and S-100b serum levels were visualized as box plots with median and percentiles (25/ 75) and 95% CI. Significance was set at P < 0.05.

Results In the hypothermia group (HG) 61 of 140 patients (43.6%) and in the normothermia group (NG) 26 of

61 patients (42.6%) survived the first 4 weeks after ROSC with moderate to good neurological outcome. In HG, the outcomes were CPC 1 = 23, CPC 2 = 27 and CPC 3 = 11, but in NG they were CPC 1 = 5, CPC 2 = 13 and CPC 3 = 8. There was no significant difference in survival rate between HG and NG. There were also no significant intergroup differences in basic resuscitation parameters (Table 2). Because of adhering to the guidelines for TH, HG patients were significantly younger than NG patients (P = 0.012), and cardiac arrest occurred more frequently in out-of-hospital area (Table 2). While in HG, mean body core temperature fell below 34°C within 4 h of ROSC (range: 33.1–33.7°C) and exceeded this limit at the earliest 28 h after ROSC on re-warming, mean body core temperature in NG was 36.5–37.5°C within the same time.18 The mean application time of hypothermia amounted to 23.9 h (± 4.97), and the target body core temperature (32.5–33.5°C) was maintained for 16.9 h (± 8.6). The duration of re-warming to a core temperature of 36°C averaged 9.1 h (± 4.8). Only on day 4, in HG, did we observe a significantly higher NSE level, and on day 5, a significantly higher S-100b serum level compared to NG. By trend, the serum levels of both proteins were lower in the NG (Fig. 1A and B). An intra-aortic balloon pump (IABP) had to be applied to 38 (27%) of HG and 11 (18%) of NG patients. IABP application was required because of cardiogenic shock or large front wall myocardial

1095

R. Pfeifer et al.

infarction and the duration of application varied. IABP can increase NSE levels by haemolysis.20 Hence, we conducted a subgroup analysis of NSE and S-100b serum levels after excluding all patients that received IABP. We did not find any significant differences in the mean serum concentrations of either protein between these subgroups (results not depicted). For NG patients with unfavourable neurological outcome (CPC 4 and 5) we found, with the exception of day 1, on each day significantly higher NSE

(A)

and S-100b serum levels compared to patients with CPC 3–1 (Fig. 2). For HG patients with CPC 4 and 5 we found on each day significantly higher NSE and S-100b serum levels compared to those with CPC 3–1 (Fig. 3). Whereas NSE serum levels peaked after 24 h and declined rapidly to normal within 48 h of ROSC in patients with good recovery, they increased continuously and considerably in patients with poor outcome and peaked on day three (Figs 2A and 3A).

(A)

(B)

(B)

Fig. 1. Box plots with median and interquartile ranges, 95% confidence interval, and outliers over a period of 5 days after return of spontaneous circulation (ROSC) of neuron-specific enolase (NSE) (A) and protein S-100b (B) serum levels. White boxes represent hypothermia group (HG) patients (n = 140) and grey boxes represent normothermia group (NG) patients (n = 61). * = significant differences between the two therapeutic groups.

Fig. 2. Box plots with median and interquartile ranges and 95% confidence interval of neuron-specific enolase (NSE) (A) and protein S-100b (B) serum levels of all normothermia group (NG) patients (n = 61). Cerebral Performance Category Scale (CPC) 3–1 = moderate to favourable neurological outcome (grey boxes); CPC 4 and 5 = unfavourable neurological outcome (white boxes). * = significant differences between the outcome groups.

1096

NSE and S-100b during hypothermia after CA (A)

(B)

were 30 such elevated levels during the first 3 days after ROSC. A total of 44 patients of both therapeutic groups survived with good outcomes (CPC 1–2) and were not treated with IABP. In 10 cases of these, NSE serum levels were > 33 ng/ml (max. 49.9 ng/ ml) during the first 3 days after ROSC. For all patients, the areas under the curve (AUC) for the ROC curves for NSE rose steadily after ROSC (Fig. 4). On days one to five, the AUCs were: 0.602, 0.831, 0.889, 0.890, and 0.892. For S-100b, however, the AUC rose steadily but fell on day five. On days one to five, these AUCs were: 0.774, 0.85, 0.875, 0.883, and 0.872. The discriminatory power of the ROC curves is therefore highest for both proteins on the third day following ROSC. On this third day, NSE levels ≥ 40 ng/ml predicted poor neurological outcome with a sensitivity 74.1% (CI: 0.6475– 0.8203), a specificity 95.2% (CI: 0.8825–0.9869), a positive predictive value (PPV) 95.2% (CI: 0.8825– 0.9869) and produce a false-positive rate (FPR) in four cases (4.8%, CI: 0.0131–0.1175). For S-100b levels ≥ 1.03 μg/l on the third day, the corresponding values were sensitivity 57.8% (CI: 0.4544– 0.6939), specificity 95.6% (CI: 0.8782–0.9909), PPV 93.2% (CI: 0.8134–0.9857) and FPR in three cases (6.8%, CI: 0.0091–0.1218).

Discussion

Fig. 3. Box plots with median and interquartile ranges and 95% confidence interval of neuron-specific enolase (NSE) (A) and protein S-100b (B) serum levels of all hypothermia group (HG) patients (n = 140). Cerebral Performance Category Scale (CPC) 3–1 = moderate to favourable neurological outcome (grey boxes); CPC 4 and 5 = unfavourable neurological outcome (white boxes). * = significant differences between the outcome groups.

The time course of S-100b serum levels is comparable to that for NSE in patients with good recovery. S-100b serum levels declined rapidly in CA survivors with moderate to good outcome, but, in patients with poor outcome, they rose continuously and also peaked on day three (Figs 2B and 3B). Taking groups together, 87 patients survived with CPC 3–1. On day 3, we found several patients with NSE serum levels of 35.4–59.9 ng/ml. These exceed the threshold of 33 ng/ml recommended as a predictor of an unfavourable outcome after CA. There

We analysed the time course of NSE and-S-100b serum levels in CA survivors that were treated either with or without TH in addition to standard intensive care therapy. The primary concern of this analysis was to investigate whether the application of TH after CA affects the serum levels of NSE and S-100b as recently suggested by several authors.12–14 We, however, did not observe improved survival rate among HG patients, which was also the case in a large controlled trial carried out in 2013.17 Nor did we see any significant reduction in NSE and S-100b serum levels by hypothermia. Rather, we found a tendency for the serum levels of both proteins to be higher in HG patients during the 5-day observation period. Moreover, there were no differences in NSE and S-100b serum levels between the two groups in a subgroup analysis. This subgroup analysis removed the potentially confusing factor of patients who had received IABP implantation, known to elevate NSE serum levels.20 The conflict between our results and those in the literature are difficult to explain. It is unlikely to be because of differences in the details of TH. We used a time to cool to the target temperature similar to

1097

R. Pfeifer et al. (A)

(B)

Fig. 4. Receiver operating characteristic curves analysis (ROC) for NSE (A) and S-100b (B) concentrations of the whole study group (n = 201) measured at different times over 5 days after ROSC (day 1–5). Areas under the curve on days 1–5 were 0.602, 0.831, 0.889, 0.89 and 0.892 for NSE, and 0.774, 0.85, 0.875, 0.883 and 0.872 for S-100b.

that in the large 2002 controlled study.1,2 The duration of hypothermia and the maintenance of the target temperature were also similar. We maintained hypothermia for 24 h, just as in the Hypothermia After Cardiac Arrest study, yet this study reported

1098

improved survival under TH.1 Survival was also improved by only 12 h hypothermia.2 Differences in hypothermia duration are therefore unlikely to affect whether or not TH reduces serum NSE and S-100b. Lower NSE serum levels in patients that have received TH than in those that have not received TH have been described.12,13 This situation contrasts markedly with our findings. In these studies, however, there were significantly more patients with favourable neurological outcome among HG patients. Such patients are well known to have significantly lower NSE and S-100b serum levels than those who die or remain comatose.5–11,21–24 We therefore suggest that the contradictions to our results arise due to the fact that these studies had an imbalance between HG and NG in the proportions of patients with good outcomes with a higher proportion in HG. The lower NSE levels are therefore not causally associated with TH. In our study, in contrast, the proportions of patients with good outcomes were the same in both HG and NG. We further think it is unlikely that the kinetics of the two proteins were changed by TH. Such an influence would affect the time course of serum concentrations in the HG. This was not the case, however, as it is clear that the time courses of their concentrations are practically identical in the two groups. They are also similar to the time courses we found in an earlier investigation of CA survivors carried out before use of TH.24 Within both, the HG and NG groups, we found significantly higher NSE and S-100b levels in patients with unfavourable outcome (CPC 4 and 5) compared to those with moderate to favourable outcomes (CPC 3–1) after 4 weeks. We calculated cut-off levels of NSE (≥ 40 ng/ml) and S-100b (≥ 1.03 μg/l) for predicting poor neurological outcome after CA with 95% specificity. Not only the question, which serum concentrations of NSE and S-100b reliably predict poor neurological prognosis after CA, is currently discussed controversially but also the question whether such cut–offs have any real utility in daily practice for predicting outcomes and making decisions following CA.25 Several authors have recently confirmed the currently recommended NSE cut-off-level of 33 ng/ml.10,11,22,23 Nevertheless, there is now increasing evidence that resuscitated patients with NSE concentrations much higher than this also survive with moderate or good neurological outcome.7,8,24–29 However, all these studies included CA survivors treated with as well as without hypothermia.

NSE and S-100b during hypothermia after CA

There are, furthermore, several factors other than CA that influence the serum concentrations of NSE levels such as haemolysis or several forms of cancer.20,21,30 For S-100b, there is little consistency. Threshold serum values over the unbelievably wide range 0.2–1.5 μg/l have been proposed as predictors of poor neurological outcome.21,23–25,28,30 Likewise, S-100b is released from tissues other than the brain such as adipocytes, chondrocytes, and several forms of cancer of the central nervous system and melanoma.20,21 Moreover, serum levels of both proteins may differ between laboratories due to a lack of standardization.31 In agreement with several other experts in the field, we were able to demonstrate that, in patients with poor neurological outcome, serum levels of NSE and S-100b increase further and remarkably after CA peaking at day three after ROSC, irrespective of TH. In contrast, the serum concentrations of both neuroproteins started to decline towards normal after as little as 2 days after ROSC in survivors with a good neurological outcome. This decrease was also found in our previous study.24 Prediction of neurological outcome on the basis of the time course of the NSE and S-100b serum levels is an interesting new approach for guiding prognosis after CA, even though available data in this field have been rare and inconsistent until now.10,23,24,26–29,32,33 Against this background, it is not at present possible to recommend a reliable cut-off level for NSE and S-100b for predicting with certainty individual neurological outcomes for CA survivors. However, in our opinion, measurement of NSE and or S-100b is a useful additional tool for making prognoses on comatose CA survivors. However, using NSE and S-100b concentrations in this way is only valid when the evaluation of serum levels of both proteins takes into consideration the limitations outlined above. We therefore recommend measuring serum levels of NSE or both proteins at least once a day during the first 5 days after ROSC.

Limitations First, this is not a randomised trial. Second, the physician on duty assigned patients to therapeutic hypothermia on the basis of the ERC recommendations. These recommendations for using TH were modified during the course of the study. Third, part way through the study, our centre participated in a Germany-wide trial that investigated hypothermia after in-hospital CA. During this trial in-hospital

CA, patients were added to our study. We are unable to exclude the possibility that our results were affected by the heterogeneity of the study population produced by these circumstances.

Conclusion This investigation demonstrates no influence of TH on NSE and S-100b serum levels in comatose CA survivors. A clear increase in both proteins over a few days after ROSC indicates poor neurological outcome. It is, however, not possible to recommend reliable threshold protein concentrations for determining unfavourable neurological outcome in comatose CA survivors. Further investigations in this field should evaluate which concentrations of these proteins are clinically useful by being able to identify the vast majority of patients with unfavourable outcome.

Acknowledgement We thank Dr Andrew Davis (English Experience, Jena, Germany) for his comprehensive revision of the English of the manuscript. Conflicts of interest: The authors declare that they have no competing interests. Funding: We have not received funding for this study.

References 1. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med 2002; 346: 549– 56. 2. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346: 557–63. 3. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck RW, Billi J, Böttiger BW, Okada K, Reyes C, Schuster M, Steen PA, Weil HM, Wenzel V, Charli P, Atkins D. International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the international Liaison Committee on Resuscitation. Circulation 2003; 108: 118–21. 4. Nolan JP, Deakin CD, Soar J, Böttiger BW, Smith G. European Resuscitation Council Guidelines for Resuscitation 2005. Section 4. Adult advanced life support. Resuscitation 2005; 1 (Suppl.): 39–86. 5. Zandbergen EG, de Haan RJ, Hijdra A. Systematic review of prediction of poor outcome in anoxic-ischemic coma with biochemical markers of brain damage. Intensive Care Med 2001; 27: 1661–7. 6. Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ, for the PROPAC Study Group. Prediction of poor outcome within the first 3 days of post anoxic coma. Neurology 2006; 66: 62–8. 7. Shinozaki K, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Abe R, Tateishi J, Hattori N, Shimada T, Hirasawa H. S-100b and neuron-specific enolase as predictors of neurological outcome in patients after cardiac arrest and return of spontaneous circulation: a systematic review. Crit Care 2009; 13: R121. doi: 10.1186/cc7973.

1099

R. Pfeifer et al. 8. Daubin C, Quentin C, Allouche S, Etard O, Gaillard C, Seguin A, Valette X, Parenti JJ, Prevost F, Ramakers M, Terzi N, Charnonneau P, du Cheyron D. Serum neuron-specific enolase as predictor of outcome in comatose cardiac arrest survivors: a prospective cohort study. BMC Cardiovasc Disord 2011; 11: 48. doi: 10.1186/1471-2261-11-48. 9. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation. Neurology 2006; 67: 203–10. 10. Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castren M, Pettilä V. Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia. Resuscitation 2009; 80: 165–70. 11. Cronberg T, Rundgren M, Westhall E, Englund E, Siemund R, Rosen I, Widner H, Friberg H. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology 2011; 16: 623–30. 12. Oddo M, Rossetti AO. Predicting neurological outcome after cardiac arrest. Curr Opin Crit Care 2011; 17: 254–9. 13. Steffen IG, Hasper D, Ploner JC, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jörres A. Mild therapeutic hypothermia alters neuron-specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care 2010; 14: R69. 14. Tiainen M, Roine RO, Pettilä V, Takkunen O. Serum neuronspecific enolase and S-100b protein in cardiac arrest patients treated with hypothermia. Stroke 2003; 34: 2881–6. 15. Zellner T, Gärtner R, Schopohl J, Angstwurm M. NSE and S-100b are not sufficiently predictive of neurological outcome after therapeutic hypothermia for cardiac arrest. Resuscitation 2013; 84: 1382–6. 16. Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvilet AC, Biemond HS, Kors BM, Koelmann JH, Verbeek MM, Weinstein HC, Hijdra A, Horn J. Prognosis after therapeutic hypothermia: a prospective cohort study. Ann Neurol 2012; 71: 206–12. 17. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Anemann A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, KØber L, LangØrgen J, Lilja G, MØller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H. Targeted temperature management at 33° versus 36°C after cardiac arrest. N Engl J Med 2013; 369: 2197–206. doi: 10.1056/NEJMoa1310519. 18. Pfeifer R, Jung C, Purle S, Lauten A, Yilmaz A, Surber R, Ferrari M, Figulla HR. Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest care. Resuscitation 2011; 82: 1168–73. 19. Jennet B, Bond MR. Assessment of outcome after severe brain damage. Lancet 1975; 1: 480–4. 20. Pfeifer R, Ferrari M, Börner A, Deufel T, Figulla HR. Serum concentration of NSE and S-100b during LVAD in nonresuscitated patients. Resuscitation 2008; 79: 46–53. 21. Scolletta S, Donadello K, Santonocito C, Franchi F, Taccone FS. Biomarkers as predictors of outcome after cardiac arrest. Expert Rev Clin Pharmacol 2012; 5: 687–99. 22. Shinozaki K, Oda S, Sadahiro T, Nakamura M, Abe R, Nakada Tanomura F, Nakiaishi K, Kitamura N, Hirasawa H. Serum S-100b is superior to neuron-specific enolase as an early prognostic biomarker for neurological outcome following cardiopulmonary resuscitation. Resuscitation 2009; 80: 870–5.

1100

23. Rundgren M, Karlsson T, Nielsen N, Cronberg T, Johnsson P, Friberg H. Neuron specific enolase and S-100b as predictors of outcome after cardiac arrest and induced hypothermia. Resuscitation 2009; 80: 784–9. 24. Pfeifer R, Börner A, Krack A, Sigusch HH, Surber R, Figulla HR. Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow Coma Scale. Resuscitation 2005; 65: 49–55. 25. Cronberg T, Brizzi M, Liedholm LJ, Rosen I, Rubertsson S, Rylander C, Friberg H. Neurological prognostication after cardiac arrest – recommendations of the Swedisch Resuscitation Council. Resuscitation 2013; 84: 867–72. 26. Fugate JE, Wijdicks EF, Mandrekar J, Classen DO, Manno EM, White RD, Bell MR, Rabinstein AA. Predictors of neurological outcome in hypothermia after cardiac arrest. Ann Neurol 2010; 68: 907–14. 27. Zingler VC, Krumm B, Bertsch T, Fassbender K, Pohlmann-Eden B. Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurobiochemical and electrophysiological investigations may provide high prognostic certainty in patients after cardiac arrest. Eur Neurol 2003; 49: 79–84. 28. Grubb NR, Simpson C, Sherwood RA, Abraha HD, Cobbe SM, O’Carroll RE, Deary I, Fox KA. Prediction of cognitive dysfunction after resuscitation from out-of-hospital cardiac arrest using serum neuron-specific enolase and protein S-100. Heart 2007; 93: 1268–73. 29. Reisinger J, Höllinger K, Lang W, Steiner C, Winter T, Zeindlhofer E, Mori M, Schiller A, Lindorfer A, Wiesinger K, Siostrzonek P. Prediction of neurological outcome after cardiopulmonary resuscitation by serial determination of serum neuron-specific enolase. Eur Heart J 2007; 28: 52–8. 30. Beaudeux JL, Leger P, Dequen L, Gandjbakhch I, Coriat P, Foglietti MJ. Influence of hemolysis on the measurement of S-100ß protein and neuron-specific enolase plasma concentrations during coronary artery bypass grafting. Clin Chem 2000; 46: 989–94. 31. Mlynash M, Buckwalter MS, Okade A, Caulfield AF, Venkatasubramanian C, Eyngorn I, Verbeeck MM, Wijman CA. Serum neuron-specific enolase levels from the same patient differ between laboratories: assessment of a prospective post cardiac arrest cohort. Neurocrit Care 2013; 19: 161–6. 32. Auer J, Berent R, Weber T, Porodko M, Lamm G, Lassing E, Mauerer E, Mayr H, Punzengruber C, Eber B. Ability of neuron-specific enolase to predict survival to hospital discharge after successful cardiopulmonary resuscitation. CJEM 2006; 8: 13–8. 33. Storm C, Nee J, Jörres A, Leithner C, Hasper D, Ploner CJ. Serial measurement of neuron-specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: a prospective study. Scand J Trauma Resusc Emerg Med 2012; 20: 6. doi: 10.1186/1757-7241-20-6.

Address: Rüdiger Pfeifer Clinic of Internal Medicine I Jena University Hospital Friedrich Schiller University Jena Erlanger Allee 101 07740 Jena Germany e-mail: [email protected]

Hypothermia after cardiac arrest does not affect serum levels of neuron-specific enolase and protein S-100b.

We investigated the brain-derived proteins neuron-specific enolase (NSE) and protein S-100b (S-100b) in survivors of cardiac arrest who had either rec...
570KB Sizes 0 Downloads 3 Views